EP1891071A2 - Cyclopropancarbonsäureester von acyclovir - Google Patents

Cyclopropancarbonsäureester von acyclovir

Info

Publication number
EP1891071A2
EP1891071A2 EP06769966A EP06769966A EP1891071A2 EP 1891071 A2 EP1891071 A2 EP 1891071A2 EP 06769966 A EP06769966 A EP 06769966A EP 06769966 A EP06769966 A EP 06769966A EP 1891071 A2 EP1891071 A2 EP 1891071A2
Authority
EP
European Patent Office
Prior art keywords
compound
formula
amino
acyclovir
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP06769966A
Other languages
English (en)
French (fr)
Other versions
EP1891071B1 (de
Inventor
David Michael Bender
James Ray Mccarthy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1891071A2 publication Critical patent/EP1891071A2/de
Application granted granted Critical
Publication of EP1891071B1 publication Critical patent/EP1891071B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention provides compounds of Formula I, pharmaceutical compositions thereof, methods of using the same, processes for preparing the same, and intermediates thereof.
  • US Patent No. 4,548,819 describes certain mono-peptide esters of acyclovir which are useful in treating virus infections. Disclosed are the glycine and alanine esters which show improved water solubility compared to acyclovir.
  • US Patent No. 4,957,924 describes a certain mono-peptide ester of acyclovir, 2(2- amino-l,6-didydro-6-oxo-9H(purin-9-yl)methoxy)ethyl L-valinate, otherwise known as valacyclovir, which shows increase in absorption from the gut compared with acyclovir and the glycine and alanine esters of acyclovir.
  • Acyclovir is limited in treating herpes simplex keratitis in part due to poor corneal permeability.
  • Valacyclovir showed improved corneal permeability compared to acyclovir.
  • valacyclovir showed poor stability in aqueous solution. The poor stability of valacyclovir renders it unsatisfactory for an ophthalmic solution.
  • Certain dipeptide esters of acyclovir showed improved solution stability at certain pH's compared to valacyclovir.
  • the present invention provides compounds of Formula I
  • R is hydrogen or C 1 - C 4 alkyl.
  • Such compounds are certain monopeptide esters, cyclopropanecarboxylate esters of acyclovir, possessing unexpected stability.
  • the present invention also provides a pharmaceutically acceptable salt form of a compound of Formula I.
  • the present invention also provides a novel pharmaceutical composition, comprising a compound of the Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention also provides a method of treating a herpes virus infection comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
  • the present invention provides a method of treating a herpes simplex or herpes zoster infection comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
  • the present invention provides a method of treating herpes simplex keratitis comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
  • the present invention also provides the use of a compound of Formula I as a medicament.
  • the present invention also provides a use of the compound of Formula I for the manufacture of a medicament for treating a herpes virus infection.
  • the present invention also provides a process for preparing a compound of Formula I 5 or a pharmaceutically acceptable salt thereof, comprising: a) for a compound of Formula I
  • R is hydrogen or C 1 - C 4 alkyl deprotecting a compound of Formula II
  • R is hydrogen or C 1 - C 4 alkyl
  • Pg is an amine protecting group
  • R is hydrogen or C 1 - C 4 alkyl
  • Pg is a amine protecting group
  • C 1 - C 4 alkyl refers to a straight or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, t-butyl and the like.
  • pharmaceutically acceptable salt refers to an addition salt that exists in conjunction with the acidic or basic portion of a compound of Formula I. Such salts include the pharmaceutically acceptable salts listed in HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, P. H. Stahl and C. G.
  • Pharmaceutically acceptable salts of an acid addition nature are formed when a compound of Formula I and the intermediates described herein containing a basic functionality are reacted with a pharmaceutically acceptable acid.
  • Pharmaceutically acceptable acids commonly employed to form such acid addition salts include inorganic and organic acids.
  • Pharmaceutically acceptable salts of a base addition nature are formed when a compound of Formula I and the intermediates described herein containing an acidic functionality are reacted with a pharmaceutically acceptable base.
  • Pharmaceutically acceptable bases commonly employed to form base addition salts include organic and inorganic bases.
  • other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically-acceptable salts, or are useful for identification, characterization or purification.
  • the term "patient” refers to a warm blooded animal such as a mammal which is infected with herpes virus.
  • a human is a preferred mammal within the scope of the meaning of the term. It is also understood that a mammal may vary to susceptibility and severity of infection.
  • the terms “treatment” and “treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the herpes virus infection and/or symptoms thereof, but does not necessarily indicate a total elimination of all symptoms or infection, and is intended to include prophylactic treatment of such.
  • the term "effective amount" of a compound of Formula I refers to an amount, that is, the dosage which is effective in treating a herpes virus infection described herein.
  • the attending diagnostician can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • the dose of a compound of Formula I a number of factors are considered by the attending diagnostician, including, but not limited to the compound of Formula I to be administered; the co-administration of other antiviral agents, if used; the species of mammal; its size, age, and general health; the specific infecting virus; the degree of involvement or the severity of the infection; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.
  • An effective amount of a compound of Formula I is expected to vary from about
  • protecting group or Pg refers to those groups intended to protect or block functional groups against undesirable reactions during synthetic procedures.
  • suitable protecting group used will depend upon the conditions that will be employed in subsequent reaction steps wherein protection is required. Commonly used amino protecting groups are disclosed in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, T. W. Greene and P.G.M. Wuts 3rd Ed. (John Wiley & Sons, New York (1999)).
  • Suitable amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and the like; substituted alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
  • Preferred suitable amino protecting groups are acetyl, methyloxycarbonyl, benzoyl, pivaloyl, allyloxycarbonyl, t- butylacetyl, benzyl, and benzyloxycarbonyl (Cbz) with t-butyloxycarbonyl (Boc) being more preferred.
  • a compound of Formula I wherein R is methyl or ethyl is preferred.
  • a compound of Formula I wherein R is hydrogen is more preferred.
  • compounds of the present invention may exist as stereoisomers. While all enantiomers, diastereomers, and mixtures thereof, are contemplated within the present invention, preferred embodiments are single enantiomers and single diastereomers.
  • the compounds of the present invention can be administered alone or in the form of a pharmaceutical composition, that is, combined with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties, including stability, of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
  • the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable salts, for convenience of crystallization, increased solubility, and the like.
  • compositions comprising a compound of the Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • a compound of Formula I may be administered by any route appropriate to condition being treated.
  • a compound of Formula I can be administered orally, by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, ocularly, topically, sublingually, buccally, and the like.
  • Oral or topical administration is generally preferred for treatment of a herpes virus infection described herein.
  • Ocular administration is preferred for the treatment of herpes simplex keratitis.
  • the pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the like.
  • a compound of the present invention may be made by a process, which is analogous to one known in the chemical art for the production of structurally analogous compounds of by a novel process described herein.
  • a compound of Formula I may be prepared from a compound of Formula II where Pg represents a suitable amine protecting group (Scheme A).
  • a compound of Formula II is reacted with reagents suitable for removing the protecting group without adversely affecting the molecule.
  • the conditions used to remove a protecting group depend on the chemical nature of the group as well as other functional groups of the compound, and are within the knowledge of the skilled artisan.
  • a compound of Formula II where Pg is t-butyloxycarbonyl is reacted within an acid such as trifluoroacetic acid in a suitable solvent such as methylene chloride to provide a compound of Formula I.
  • a compound of Formula II where Pg is an amino protecting group may be prepared from acyclovir and a compound of Formula III where Pg represents a suitable amino protecting group (Scheme B).
  • acyclovir is combined with a compound of Formula III under acylation reaction conditions.
  • acylation reactions to transfer a compound of Formula III encompass an ester formation reaction similar to those which are conventionally conducted in the art and synthetic methods used therein can also be employed.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. may be used to facilitate ester formation.
  • the reaction may also be performed in the presence of a base such triethylamine.
  • reaction is conveniently conducted in an inert aprotic solvent such as pyridine, dimethylformamide, dichloromethane, chloroform, 1,2- dichloroethane, acetonitrile, tetrahydrofuran and the like.
  • aprotic solvent such as pyridine, dimethylformamide, dichloromethane, chloroform, 1,2- dichloroethane, acetonitrile, tetrahydrofuran and the like.
  • the present invention provides cyclopropanecarboxylate esters of acyclovir, a compound of Formula I, with unexpected stability to acid and base conditions.
  • a compound of Formula I wherein R is hydrogen shows a greater half-life compared to valacyclovir when incubated in aqueous solution at a pH of 6, 8 or 10 (Table A). This unexpected stability provides an advantage when formulating a pharmaceutical composition comprising an aqueous vehicle such as that of an ophthalmic solution.
  • Test samples of valacyclovir and 1-amino-cyclopropanecarboxylic acid 2-(2- amino-6-oxo-l,6-dihydro-purin-9-ylmethoxy)-ethyl ester trifluoroacetic acid salt (Example 1) are dissolved in buffered solutions of known pH at a concentration of 100 mcg/mL.
  • Compound samples are prepared in 0.1 N hydrochloric acid for pH 1 and phosphate based buffer for pH 2, 4, 6, 8 and 10. Stability is conveniently assessed using a semi-automated HPLC technique.
  • Compound samples are loaded onto an HPLC autosampler incubated at 4O 0 C. Samples are repeatedly injected on the HPLC at specific time intervals. The peak area of the compound samples are monitored by XJV detection.
  • the HPLC system consisted of an Agilent® 1100 autoinjector, pump, degasser and UV detector.
  • a Waters® Atlantis dC-18 column (3micron, 150 x 4.6 mm LD.) is used to separate the degradation products from the compound sample.
  • An isocratic reversed-phase system using ultraviolet detection is used to monitor the peak areas of the compound sample over a 24 hour period.
  • the mobile phase composition is 5% acetonitrile and 95% water with 0.1% trifmoroacetic acid added to the mixture.
  • the flow rate is 1.5 niL/min.
  • the column temperature is 30 degrees Celsius and the injection volume was 10 ⁇ L.
  • the UV detector is set at 256nm and the run time was 9 minutes. Time points are analyzed every 2 hours for each buffer while being incubated at 40 degrees Celsius by the thermostat controlled autosampler.
  • the peak area of the compound sample is monitored over a 24 hour period at 2 hour intervals.
  • the peak area of the compound sample is plotted versus time for each of the buffers tested.
  • a first order calculation is used to determine the rate constant for each buffer based on the loss of peak area over time.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
EP06769966A 2005-05-25 2006-05-04 Cyclopropancarbonsäureester von acyclovir Expired - Lifetime EP1891071B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68449305P 2005-05-25 2005-05-25
PCT/US2006/016830 WO2006127217A2 (en) 2005-05-25 2006-05-04 Cyclopropanecarboxylate esters of acyclovir

Publications (2)

Publication Number Publication Date
EP1891071A2 true EP1891071A2 (de) 2008-02-27
EP1891071B1 EP1891071B1 (de) 2012-02-22

Family

ID=37008813

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06769966A Expired - Lifetime EP1891071B1 (de) 2005-05-25 2006-05-04 Cyclopropancarbonsäureester von acyclovir

Country Status (5)

Country Link
US (1) US7846937B2 (de)
EP (1) EP1891071B1 (de)
AT (1) ATE546451T1 (de)
ES (1) ES2379804T3 (de)
WO (1) WO2006127217A2 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009221761A1 (en) 2008-03-07 2009-09-11 Ray W. Exley Treatment of herpes virus related diseases
IN2014MN02105A (de) * 2012-04-20 2015-09-11 Annji Pharm Co Ltd

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4199574A (en) 1974-09-02 1980-04-22 Burroughs Wellcome Co. Methods and compositions for treating viral infections and guanine acyclic nucleosides
NL8202626A (nl) 1982-06-29 1984-01-16 Stichting Rega V Z W Derivaten van 9-(2-hydroxyethoxymethyl)guanine.
AP160A (en) 1987-08-15 1991-11-18 The Wellcome Foundation Ltd Therapeutic acyclic nucleosides.
GB8719367D0 (en) * 1987-08-15 1987-09-23 Wellcome Found Therapeutic compounds
US5543414A (en) * 1994-07-28 1996-08-06 Syntex (Usa) Inc. Achiral amino acid acyl esters of ganciclovir and its derivatives
GB9501127D0 (en) 1995-01-20 1995-03-08 Wellcome Found Tablet
GB9501178D0 (en) 1995-01-20 1995-03-08 Wellcome Found Guanine derivative
US20030114460A1 (en) * 2001-12-14 2003-06-19 Allergan Sales, Inc. Pharmaceutical conjugates with enhanced pharmacokinetic characteristics
AU2009221761A1 (en) * 2008-03-07 2009-09-11 Ray W. Exley Treatment of herpes virus related diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006127217A2 *

Also Published As

Publication number Publication date
ES2379804T3 (es) 2012-05-03
WO2006127217A3 (en) 2007-02-22
EP1891071B1 (de) 2012-02-22
WO2006127217A2 (en) 2006-11-30
US20090270428A1 (en) 2009-10-29
US7846937B2 (en) 2010-12-07
ATE546451T1 (de) 2012-03-15

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